Recombinant human growth hormone (rhGH) long-acting sustained-release microcapsule and preparation method thereof

A human growth hormone, sustained-release technology, applied in the field of medicine, can solve the problems of aggravating side effects, producing immunogenicity, low bioavailability, etc., and achieves the effect of maintaining sustainable release, maintaining biological activity, and improving the encapsulation rate

Active Publication Date: 2012-03-14
INST OF PROCESS ENG CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Chinese patent (publication number CN1187120) also discloses a method for preparing and using a sustained-release human growth hormone (hGH) composition, which solves the problem of providing subjects with sustained-release therapeutically effective blood level doses of hGH within one month, But need to use metal ion zinc Zn 2+ Stable growth hormone meets the requirements of sustained release, and the preparation process is complicated; in addition, due to the addition of Zn in the preparation process 2+ , which brings difficulties to the determination and removal of residues, which is not conducive to large-scale industrial production
This higher burst release causes the blood drug concentration to be too high, exceeding the effective use concentration, resulting in excessive drug concentration in the body causing or aggravating side effects; and causing drug waste, resulting in the sustained release of the drug that cannot reach the effective concentration in the later stage
In general, when preparing recombinant human growth hormone-loaded sustained-release microcapsules, the microcapsules prepared by the prior art have uneven particle size, poor reproducibility, and low bioavailability; protein drugs are prone to aggregates during the preparation and release process (more than 15% is obvious aggregation), resulting in immunogenicity and loss of activity; additional excipients are required to obtain a higher drug embedding rate and sustainable release, resulting in difficulties in the determination of residual residues in the later stage and reduced biological safety

Method used

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  • Recombinant human growth hormone (rhGH) long-acting sustained-release microcapsule and preparation method thereof
  • Recombinant human growth hormone (rhGH) long-acting sustained-release microcapsule and preparation method thereof
  • Recombinant human growth hormone (rhGH) long-acting sustained-release microcapsule and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] The hydrophilic SPG membrane with a pore size of 5.2 μm was soaked in water to fully wet the porous membrane. 0.8mL concentration is 40mg / mL recombinant human growth hormone (rhGH) aqueous solution as inner water phase (W 1 ), 0.4 g of polylactic acid-polyethylene glycol copolymer (PELA) with a molecular weight of 30,000 was dissolved in 8 mL of ethyl acetate as the oil phase (O). Mix the inner water phase and the oil phase, homogeneously emulsify for 30s, and get W 1 / O colostrum. The colostrum was added to 48 mL of 1% wt polyvinyl alcohol (PVA) aqueous solution (W 2 ), magnetically stirred at 300rpm for 1min to prepare pre-double emulsion (W 1 / O / W 2 ), and then press the pre-complex emulsion under the operating pressure of 300kPa through the microporous membrane device (such as figure 1 ) to obtain a multiple emulsion, the emulsion film-passing time is less than 10s, then the multiple emulsion is stirred at room temperature with 0.9% NaCl of 1L for 4h to extract...

Embodiment 2

[0069] The hydrophilic SPG membrane with a pore size of 0.5 μm was soaked in water to fully wet the porous membrane. 1.0mL concentration is 100mg / mL recombinant human growth hormone (rhGH) aqueous solution as inner water phase (W 1 ), 0.2g of polylactic acid-polyethylene glycol copolymer (PELA) with a molecular weight of 10,000 and 0.2g of 20,000 was dissolved in 8mL of propyl acetate as the oil phase (O). Mix the inner water phase and the oil phase, homogeneously emulsify for 15s, and obtain (W 1 / O) type colostrum. This colostrum is added in the 1%wt PVA aqueous solution of 48mL, magnetic stirring 300rpm stirs 1min and prepares pre-double emulsion (W 1 / O / W 2 ), then press the pre-multiple emulsion through the microporous membrane device under the operating pressure of 2000kPa to obtain the multi-emulsion, the emulsion passing time is less than 10s, then under the room temperature of the multi-emulsion, stir 4h with 0.9% NaCl of 1L to extract ethyl acetate ester, and the...

Embodiment 3

[0071] The hydrophilic membrane with a pore size of 1.4 μm is soaked in water to fully wet the porous membrane. Dissolve 0.4g of polycaprolactone and polyethylene glycol copolymer with a molecular weight of 20,000 in 8mL ethyl propionate as the oil phase (O), mix 120mg of recombinant human growth hormone (rhGH) solid particles with the oil phase Mix and homogeneously emulsify for 15 seconds to obtain (S / O) type colostrum. This colostrum is added in the 1%wt PVA aqueous solution of 48mL, magnetic stirring 300rpm stirs 1min and prepares pre-double emulsion (S / O / W 2 ), and then press the pre-multiple emulsion through the microporous membrane device under the operating pressure of 800kPa to obtain the multi-emulsion, the emulsion passing time is less than 10s, then under the room temperature of the multi-emulsion, stir 4h with 0.9% NaCl of 1L to extract ethyl acetate ester, and then centrifuged to obtain drug-loaded microcapsules. The obtained microcapsules were vacuum-dried for...

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Abstract

The invention relates to the field of medicine, and specifically, relates to a recombinant human growth hormone (rhGH) long-acting sustained-release microcapsule and a preparation method thereof. The preparation method of the rhGH long-acting sustained-release microcapsule comprises the following steps of 1, dissolving a diblock amphiphilic polymeric material in an organic solvent to obtain an oil phase O, 2, adding an rhGH-containing aqueous solution W1 or rhGH-containing particles S into the oil phase O obtained by the step 1, and carrying out emulsification preparation to obtain W1 / O or S / O primary emulsion, wherein the rhGH-containing aqueous solution W1 is utilized as an inner water phase, 3, adding the W1 / O or S / O primary emulsion into a stabilizer-containing outer water phase W2 to obtain W1 / O / W2 or S / O / W2 composite pre-emulsion, 4, carrying out a filter pressing process on the W1 / O / W2 or S / O / W2 composite pre-emulsion through a millipore membrane to obtain W1 / O / W2 or S / O / W2 composite emulsion, and 5, removing the organic solvent in the W1 / O / W2 or S / O / W2 composite pre-emulsion, carrying out solidification, centrifugal washing and freeze drying of the organic solvent-free W1 / O / W2 or S / O / W2 composite emulsion. The rhGH long-acting sustained-release microcapsule obtained by the preparation method has the advantages of even size, high encapsulation efficiency, high activity, low burst release quantity, good repeatability, simpleness of operation, and benefit to drug effect activity keeping and industrialized mass production.

Description

technical field [0001] The invention relates to the field of medicine, in particular to recombinant human growth hormone rhGH long-acting slow-release microcapsules and a preparation method thereof. Background technique [0002] Recombinant human growth hormone (rhGH) is widely used clinically to treat various diseases such as dwarfism, severe burns, and lipodystrophy in AIDS patients. The half-life in the body is short (0.5 hours), and there is an urgent need to develop rhGH long-acting sustained-release preparations . The traditional preparation method of rhGH microcapsules is mainly mechanical stirring or using a homogenizer. The particle size of the prepared microcapsules is very large, reaching tens or even hundreds of microns, and the size is uncontrollable. Inhomogeneous particle size leads to uneven distribution of drugs in small particle size microcapsules, which makes it difficult to improve the embedding rate, and will inevitably cause poor repeatability of prepa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/66A61K38/27A61K47/34A61P3/00A61P17/02
Inventor 马光辉韦祎王玉霞苏志国周炜清
Owner INST OF PROCESS ENG CHINESE ACAD OF SCI
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